PROJECT SUMMARY/ABSTRACT Alzheimer?s Disease (AD) is the 6th leading cause of death in the United States, and is estimated to cost more than $200B/year.Uniquelyamongthetoptencausesofdeath,wehavelittleabilitytotreatorpreventthedisease.Although the precise etiology of AD is still under investigation, strong evidence suggests a causative role for systemic inflammation. The Jasper lab and others have shown that a healthy microbiome is essential for regulating intestinal inflammation.ArecentstudydemonstratedreducedA?plaquedepositionandmicroglialactivitywhentreatingamouse AD model with long?term antibiotics, suggesting that inflammation related to commensal bacteria could regulate diseaseprogression. My preliminary data indicates that inflammatory cytokines from the Drosophila intestine reach the CNS and activate JAK/STAT signaling in a subset of glial cells. Reducing intestinal loads ameliorates this signaling, reduces aggregate formationandneurodegenerationinaflymodelofAD,andimproveshealthandsurvival.Here,Iproposeamechanistic studytodelineatethesignalingpathwaysandphysiologicalconsequencesofintestinalinflammationreachingthebrain. My hypothesis is that commensal bacteria can induce secretion of cytokines from the intestine into the (blood? analogous)hemolymph,promotingneurodegenerativeprocessesinbrainsburdenedwiththeamyloidpeptideA?42.My research aims will establish how intestinal stress triggers inflammatory signaling and determine the nature of the responsive glial cells in the brain. I will further establish the connection between this inflammatory response and A? plaques,andapplybothgeneticandpharmaceuticalinterventionstoreduceintestinalinflammationandtherebyreduce thephenotypesoftheADmodel. My mentoring team consists of Prof. Heinrich Jasper, an expert on the Drosophila intestine and stress signaling, Prof. PejmunHaghighi,anexpertonDrosophilaneurobiology,andProf.DaleBredesen,anexpertonAD.WiththeirguidanceI willdeveloptheconceptualunderstandingofneurobiologyandAD,aswellasthetechnicalskills,requiredtocarryout this project and establish an independent research program. Their assistance will furthermore be invaluable in my transitiontoindependenceasascientist,asdescribedinmycareerdevelopmentplan.